The myotonic muscular dystrophy (DM) disease is the most common adult muscular dystrophy in man with a prevalence of 1 in 10,000. The disorder is inherited in an autosomal dominant manner with variable expression of symptoms from individual to individual within a given family. Furthermore, the phenomenon of anticipation (increasing disease severity over generations) is well documented for DM. This is particularly evident when an affected mother transmits the gene for the disease to her offspring. These offspring have a high incidence of mental retardation and profound infantile myotonia. Adult patients with DM manifest a pleiotropic set of symptoms including myotonia, cardiac arrhythmias, cataracts, frontal baldness, hypogonadism, and other endocrine dysfunctions. There is no evidence that myotonic muscular dystrophy may be caused by defects in more than one gene.
A myotonic muscular dystrophy gene has been mapped to human chromosome position 19q13.3. Both a genetic and physical map of the region was developed by a group of investigators acting as a voluntary consortium under sponsorship of the Muscular Dystrophy Association. The genetic linkage studies identified two RFLP alleles, D10 and X75, which are polymerase chain reaction (PCR)-based dinucleotide polymorphisms and are tightly linked to DM.
Two disorders, Kennedy disease and fragile X syndrome, are associated with triplet nucleotide amplification. The triplet is CAG in the Kennedy disease gene and CGG in the fragile X syndrome gene. Repeat lengths in Kennedy disease have been reported as 40-57 units, whereas the normal range is 11-31 repeats. In the case of fragile X syndrome, the CGG repeat sequence becomes unstable once greater than 52 units long and is predisposed to amplification during female meiosis. The molecular basis of the Sherman paradox has now been explained for fragile X syndrome. The generation-to-generation progressive amplification of the CGG triplet repeat in fragile X syndrome correlates with increasing disease severity and lack of expression of the FMR-1 gene.
The present application provides a new method of sequence scanning for triplet repeats which are GC-rich and thus suspect for genetic instability by amplification/deletion/translocation. This method successfully identified a putative protein kinase gene in patients with DM. This application also provides rapid and simple methods for accurate means of DM diagnosis. The gene, myotonin protein kinase, was discovered by molecular cloning, predicted to be a protein kinase on the basis of sequence motif homology, characterized with regard to its sequence and alternative spliced forms, and found to be altered in expression in tissues of patients with DM.